5-Fluorouracil (5-FU) is an effective enhancer of
radiation therapy (RT) in head and
neck cancers. Due to rapid, predominantly hepatic metabolism by
dihydropyrimidine dehydrogenase (DPD) and suggested clinical benefit from prolonged
drug exposure,
5-FU is commonly given by continuous infusion.
Eniluracil is a novel DPD-inactivator designed to prolong the half-life of
5-FU and provide sustained plasma concentrations of
5-FU with oral dosing. We conducted a Phase I study of the safety and efficacy of
eniluracil given with oral
5-FU in patients receiving concurrent RT for recurrent or advanced
squamous cell carcinomas of the head and neck. Thirteen patients with recurrent, metastatic, or high-risk (defined as an expected 2-year survival rate of <10%)
head and neck cancer were enrolled and treated with
concomitant chemoradiotherapy on an every-other-week schedule.
Eniluracil at a fixed dose [20 mg twice a day (BID)] was given for 7 consecutive days (days 1-7).
5-FU and RT were given on 5 consecutive days (days 2-6). One patient was treated with once-daily RT (2.0 Gy fractions). The remaining patients received hyperfractionated RT (1.5-Gy fractions BID). The initial dose of
5-FU was 2.5 mg/m2 given BID. Dose escalation in patient cohorts was scheduled at 2.5-mg/m2 increments, with intrapatient dose escalation permitted. Lymphocyte DPD activity and serum
5-FU and
uracil concentrations were monitored during two cycles. DPD activity was completely or nearly completely inactivated in all patients. Sustained, presumed therapeutic concentrations of
5-FU were observed at a dose of 5.0 mg/m2 given BID. Cumulative dose-limiting myelosuppression (both
neutropenia and
thrombocytopenia) was observed during the fourth and fifth cycles following administration of 5.0 mg/m2
5-FU BID. One patient died of neutropenic
sepsis during cycle 4. Other late cycle toxicities included
diarrhea,
fatigue, and
mucositis. Grade 3
mucositis was observed in 4 patients, but no grade 4
mucositis or grade 3 or 4
dermatitis was observed. A second patient death occurred during cycle 1 of treatment. No specific cause of death was identified. The study was subsequently discontinued. Cumulative myelosupression was the significant dose-limiting toxicity of oral
5-FU given with the DPD-inactivator
eniluracil on an every-other-week schedule. Clinical radiation sensitization was not observed, based on the absence of dose-limiting
mucositis and
dermatitis. Alternative dosing schedules need to be examined to determine the most appropriate use of
eniluracil and
5-FU as radiation enhancers.